Ozonolysis hydrazones

Metalated SAMP- or RAMP-hydrazones derived from alkyl- or arylethyl ketones 3 add to arylaldehydes both diastereo- and enantioselectively. Substituted / -hydroxy ketones with relative syn configuration of the major diastereomer are obtained with de 51-80% and 70-80% ee. However, recrystallization of the aldol adducts, followed by ozonolysis, furnishes diastereo- and enantiomerically pure (lS, S )-. yn-a-mcthyl-/3-hydroxy ketones 5 in 36-51% overall yield. The absolute configuration of the aldol adducts was established by X-ray crystallographic analysis. Starting from the SAMP- or RAMP-hydrazone either enantiomer, (S,S) or (R,R), is available using this methodology16. 

The aldehyde or ketone functionalities in the Michael adducts are restored by ozonolysis of the hydrazone moiety resulting in am/-3,4-disubstituted-5-oxoalkanoates 1. 

An excellent synthetic method for asymmetric C—C-bond formation which gives consistently high enantioselectivity has been developed using azaenolates based on chiral hydrazones. (S)-or (/ )-2-(methoxymethyl)-1 -pyrrolidinamine (SAMP or RAMP) are chiral hydrazines, easily prepared from proline, which on reaction with various aldehydes and ketones yield optically active hydrazones. After the asymmetric 1,4-addition to a Michael acceptor, the chiral auxiliary is removed by ozonolysis to restore the ketone or aldehyde functionality. The enolates are normally prepared by deprotonation with lithium diisopropylamide. 

In contrast to the Johnson s D —> A-ring construction approach, Brown devised an A —> D-ring construction approach [22]. Starting from Wieland-Miescher ketone (30), a common source of the A, B-rings in the de novo synthesis of steroids, the C-ring was introduced via hydrazone allylation, ozonolysis, aldol condensation, and olefin isomerization (31 > 32). The D-ring was assembled by a reductive alkylation... 

Enantioselective a-hydroxylotion of carbonyl compounds. The lithium enolates of the SAMP-hydrazones of ketones undergo facile and diastereoselective oxidation with 2-phenylsulfonyl-3-phenyloxaziridine (13, 23-24) to provide, after ozonolysis, (R)-a-hydroxy ketones in about 95% ee. High enantioselectivity in hydroxylation of aldehydes requires a more demanding side chain on the pyrrolidine ring such as —QCjHOjOCH, which also results in reversal of the configuration. 

SAMP/RAMP-Hydrazones are cleaved oxidatively by ozonolysis in dichloromethane at — 78 °C3. This method proceeds within 15 to 30 minutes/10 mmol in quantitative yield without racemization. The endpoint of the cleavage reaction is indicated by the green color of the yellow nitrosamine with blue ozone. Besides the desired carbonyl compound, one quivalent of (S)- or (/J)-2-methoxymethyl-l-nitrosopyrrolidine is formed. 

Enders et al.173) transformed open chain and cyclic P-ketoesters into the corresponding SAMP-hydrazones. Metalation with n-butyllithium, followed by trapping of the intermediate anions with alkyhalides generates esterhydrazones which upon cleavage by ozonolysis finally leads to optically active p-ketoesters. While the overall chemical yields are good, the enantiomeric excesses of 18-60% are relatively low. 

In continuation of our efforts to explore the utility of the SAMP/RAMP hydra-zone methodology, we developed the first asymmetric synthesis of a-phosphino ketones via formation of a carbon-phosphorus bond in the a-position to the carbonyl group [70]. The key step of this asymmetric C—P bond formation is the electrophilic phosphinylation of the ketone SAMP hydrazone 87, giving rise to the borane-adduct of the phosphino hydrazone 88 with excellent diastereoselectiv-ity (de = 95-98%). Since these phosphane-borane adducts are stable with respect to oxidation, the chemoselective cleavage of the chiral auxiliary by ozonolysis leading to the a-phosphino ketones (R)-89 could be accomplished with virtually no racemization. Using RAMP as a chiral auxiliary, the synthesis of the enantiomer (S)-89 was possible (Scheme 1.1.25). 

An alternative access was achieved by alkylation of the a-diphenylphosphino acetaldehyde SAMP hydrazone 95, yielding the hydrazone products 96 in good yields (60-63%) and good diastereomeric excesses (die = 68-71%) as EjZ mixtures, from which the major diastereomer was separated and purified by preparative HPLC. Ozonolysis and in-situ reduction with the borane-dimethyl sulfide complex of the aldehydes generated gave the air-stable borane-protected 2-diphenylphosphino alcohols 97 in good yields (67-83%). Reaction with DABCO afforded the unprotected 2-phosphino alcohols 98 in very good yields (85-91%) and excellent enantiomeric excesses (ee > 96%) (Scheme 1.1.27). 

Besides the oxidative cleavage by ozonolysis, the optically active carbonyl compounds can be alternatively obtained by acidic hydrolysis of the corresponding SAMP-/RAMP-hydrazone methiodides in a two-phase system. > a... 

We were also interested in the possibility of synthesizing derivatives modified in both the carboxylic acid side chain and ketone bearing side chain the resulting tetracyclic analogues of artemisinin would then be modified at both C-3 and C-9. As the requisite ketal(s) were available,83 their deketalization, hydrazone formation, alkylation, and subsequent ozonolysis and cyclization were explored as shown in Scheme 5. 

To complete the reaction sequence of Figure 13.35, the desired alkylated ketone needs to be released from the kethydrazone. Ozonolysis cannot be used in the present case. Ozonoly-sis would cleave not only the C=N double bond but also the C=C double bond. Another method must therefore be chosen. The kethydrazone is alkylated to give an iminium ion. The iminium ion is much more easily hydrolyzed than the hydrazone itself, and mild hydrolysis yields the deshed -enantiomer of 6-methyl-2-cyclohexenone. The other product of hydrolysis is a RAMP derivative. This RAMP derivative carries a methyl group at the N atom and cannot be recycled to the enantiomerically pure chiral auxiliary A that was employed initially. 

Asymmetric Michael additions The anions of hydrazones (2), obtained from 1 and methyl ketones, undergo conjugate addition to a,p-unsaturated esters with virtually complete 1,6-asymmetric induction to give the adducts (S,R)-3. Ozonolysis converts these products into P-substituted 8-keto esters, (R)-4, obtained in optical yields of 96-l(X)%, with recovery of the chiral auxiliary as the nitrosamine (S)-5. The overall chemical yields of 4 are 45-62%. 

Resolution of a-substituled aldehydes. The SASP hydrazones of a-substituted aldehydes can be resolved by high-performance liquid chromatography. The separahility factors are sufficient for analytical and preparative purposes. The (S,S)-isomer elutes consistently before the (S,R)-isomer. Both isomers can be cleaved to the enantiomerically pure aldehydes by ozonolysis or acid hydrolysis, with resolution yields of 35-70%. 

Vinylsilanes may be prepared from the corresponding ketones by formation of the hydrazone followed by Shapiro reaction, quenching the vinylic anion with chlorosilanes. An equally effective process derives the vinylsilane from the vinyl chloride, in turn prepared simply from the ketone. The crucial oxidative transformation may be achieved in two ways. Firstly, ozonolysis in dichloromethane/methanol at approximately 0 C followed by reductive work-up affords the a-hy xy ketone, e.g. (96) to (97), via the intermediates (98) and (99). The outcome of the reaction varies with the solvent and work-up conditions, but using the combination indicated, good yields of the desired products are available. 

Enders and Bhushan reported the preparation of a-benzyloxy aldehydes and a-acetoxy ketones 6 of high enantiomeric purity and in good overall yield by oxygenation of the azaenolates of chiral hydrazone 4 with 3-phenyl-2-(phenylsulfonyl)oxaziridine 282. The chiral auxiliary was removed without racemization by ozonolysis of the a-hydroxy hydrazone 5 at — 78 °C. 

Michael addition of trialkylstannyllithium to cyclohexenone SAMP- or RAMP-hydrazone gives 3-stannyl derivatives with de values of 42-44%, while subsequent alkylation of the enolate formed affords trans-products with de values >96%. The hydrazones obtained are subjected to ozonolysis to give 3-stannylcyclohexanones trans-1 with ee values up to 96%17. 

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